Pancreatic cancer is characterized by dense stroma consisting of myofibroblasts, abundant extracellular matrix (ECM) and inflammatory/immune cells. Elevated levels of transforming growth factor β (TGFβ), a prominent driver of stromal accumulation, is a negative prognostic indicator for pancreatic cancer patients. However, inhibition of TGFβ has been challenging due to the context-dependent tumor suppressor function of TGFβ in pancreatic cancer. We reported previously that neutralizing the activity of murine TGFβ receptor 2 (Tgfβr2) using a monoclonal antibody (2G8), has potent antitumor activity in orthotopic human pancreatic tumor xenografts. The findings in xenografts highlight that TGFβ induction of stromal cell function is critical for its impact on tumor cell behavior and PDA progression and supports that inhibition of TGFβ-dependent effector functions on stromal cells has potential efficacy in PDA. Herein we demonstrate that inhibition of murine Tgfβr2 reduces IL-6 production from cancer-associated fibroblasts (CAFs), resulting in a reduction of Stat3 activation in tumor cells and reversion of the immunosuppressive landscape of murine models of PDA. Moreover, the reduction of stromal IL-6 results in activation of NK cells. In summary, we found TGFβ induced IL-6 secretion from CAFs in PDA contributes to tumorigenesis and immunosuppression and can be abrogated by inhibition of stromal Tgfβr2.

Citation Format: Huocong Huang, Moriah Hagopian, Wenting Du, Yuqing Zhang, Kyla E. Driscoll, Rolf A. Brekken. Targeted inhibition of Tgfβr2 reduces IL-6 production from cancer-associated fibroblasts, suppresses Stat3 activation in pancreatic cancer cells and reverses immunosuppression [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B68.

©2018 American Association for Cancer Research.
2018
American Association for Cancer Research.